In the attempt to generate a suitable animal model we have taken a novel approach of "reverse conditional gene targeting", in which TrkA is deleted only in non-neuronal cells (Coppola et al.. 2004) With this mutation we could show that the NGF receptor TrkA is not required for development of the immune system. However, TrkA deficiency causes defects associated with a specific class of B lymphocytes and immunoglobulin production as well as degranulation defects in mast cells. Thus, TrkA, appears to modulate functions of the immune system rather than its development. This was a striking result since many studies suggested that disruption of the NGF/TrkA system in the immune system would cause dramatic deficits. Currently, we are in the process of performing more functional studies in vivo using this reverse conditional TrkA mutant mouse model. Having validated the use of this new reverse conditional strategy to specifically restore a gene function in a specific organ, we have now generated a similar mouse mutant for the TrkB gene. Analysis of this mutant is underway. These experiments should help elucidate the function of Trk genes in the non-neuronal compartments.